4-androstene-2alpha, 3, 17beta-triols and preparation thereof



3,081,318 Patented Mar. 12, 1963 3,081,318 4-ANDROSTENE-2a,3,17p-TR1 LSAND PREPARATION THEREOF Robert L. Clarke, Bethlehem, N.Y., assignor toSterling Drug Inc., New York, N.Y., a corporation of Delaware NoDrawing. Filed Nov. 18, 1959, Ser. No. 853,679 7 Claims. (Cl. 260-3975)This invention relates to steroid triols and in particular is concernedwith 4-androstene-2a,3,17,8-trio1s and the preparation thereof.

The compounds of the invention have the structural formulas:

CH: 0 H3 I II wherein R represents hydrogen or a carboxylic acylradical.

:When 'R-fin the 'above structural formulas represents carboxylicec yl,it stands for carboxylic acids having from one to about ten carbonatoms, conventionally employed in the steroid art, and having amolecular weight less than about 200. Representative of the 'acylradicals which can be present are lower-alkanoyl radicals, e.g., formyl,acetyl, propionyl, butyryl, isobutyryl, caproyl, heptanoyl, octanoyl,trimethylacetyl, and the like; carboxy-lower-alkanoyl radicals, e.g.,succinyl (,B-carboxypropionyl); cycloalkyl-lower-alkanoyl radicals,e.g., B-cyclopentylpropionyl, fi-cyclohexylpropionyl, and the like;monocarbocyclic aroyl radicals, e.g., benzoyl, p-toluyl, p-nitrobenzoyl,3,4,5-triinethoxybenzoyl, and the like; monocarbocyclicaryl-lower-alkanoyl or -alken0y1 radicals, such as phenylacetyl,8-phenylpropionyl, cinnarnoyl, and the like; and monocarbocyclicaryloxy-lower-alkanoyl radicals, such as p-chlorophenoxyacetyl, and thelike.

The compounds of the invention are prepared by reduction of the known2a,1713-dihydroxy-4-androsten-3 one [Clarke et al., J. Am. Chem. Soc.77, 661-4 (1955)] with lithium aluminum hydride. The reduction takesplace readily at room temperature in an inert, anhydrous solvent such asether, petroleum ether, benzene, or the like. The product is isolated byhydrolysis and extraction, and separated into the two C -epimers,4androstene-2ot, 3a,17B-triol (I; R H) and 4-androstene2u,3fl,l7fiatriol(II; R=H) by fractional crystallization. Triesters of the two triols areprepared by conventional procedures by reacting them with theappropriate acid anhydride or acid halide.

The structures of the compounds of the invention were established by themethod of preparation, by elementary analysis and by the method ofoptical rotatory differences. Conversions of20t-hYCllOXY-4-ChOlBStfiIl-3-0l'le acetate to 4-cholestene-2a,3fi-dioldiacetate is accompanied by a molecular rotational change (AM of 585.The analogous conversion in the present series, 2a,17/8-dihydroxy-4-androsten-3-one diacetate to the epimeric4-androstene-2oz,3,17B-triol triacetates, involves molecular rotationalchanges of +302 and 605. The triacetate which showed the 605 change,namely the one melting at 151.2-153.2 C., was assigned the 2a,3fi,17[3-configuration. In further support of the above structural assignments,conversion of 4-cholestene-2a,3B-diol to its diacetate is accompanied bya AM of -448. Analogously, conversion of 4-androstene-2a,3,8,l7fi-triolto its triacetate involves a AM of 422 which, when modified by a AM of30 due to the esterification of the 17fi-hydroxy group, gives acorrected value of --392. On the other hand, conversion of the4-androstene-2a,'3u,

l7fi-triol to its triacetate involves a AM of -9l which,

when modified for the C esterification, gives a corrected value of --6l.

Endocrinological studies of the compounds of the invention have shownthat they possess useful metabolic, hormonal and antihormonalproperties. In particular, they exhibit anabolic and estrogen-inhibitingactivities. They can be prepared for use by dispersing them in anaqueous suspension or by dissolving them in a pharmacologicallyacceptable oil or oil-water emulsion for parenteral administration; orby incorporation in tablet form with excipients for oral administration.

The following examples will illustrate the invention without the latterbeing limited thereby.

EXAMPLE 1 Reduction of 2a,]7B-dihydroxy-4-andr0sten-3-0ne.-A solution of1.17 g. (0.0038 mole) of 2a,l7fl-dihydroxy- 4-a-ndrosten-3-one in 300ml. of ether was added to a was chilled. The solid which separated wasrecrystallized from acetone to give 123 mg. of 4-androstene2ot,3a,1718-triol in the form of colorless needles, M.P. 248.8- 251.9 C.(corn), [a] =+246.9i0.6 (1% in ethanol), M =+756.

Analysis.-Calcd. for 0 1-1 0 C, 74.5; H, 9.9. Found: C, 74.5; H, 9.8.

The mother liquors from the crystallization of4-androstene-2a,3a,17B-triol obtained above were concentrated to a 15ml. volume and allow to stand at 25 C. The solid product which separatedwas collected and recrystallized from acetone to give 142 mg. of4-androstene- 2a,3B,17,8-triol in the form of heavy needle clusters,M.P. 199.9201.2 C. (corn), [a] =+26.3- -0.7 (1% in 95% ethanol), M=+8O.4.

Analysis.-Calcd. for C I-1 0 C, 74.5; H, 9.9. Found: C, 74.5; H, 9.6.

EXAMPLE 2 2a,3u,17fl-triacetoxy-4-androstene.-A mixture of 0.68 g. of4-androstene-2a,3a,175-triol and 5 ml. of acetic anhydride was heated ona steam bath for three and onehalf hours. The product was isolated andrecrystallized from ether to give 0.64 g. of2a,?)a,17p-triacetoxy-4-androstene in the form of colorless needles,M.P. 175.2- 179.2 C. (corn), [a] =+153.5i0.2 (1% in 95% ethanol), M=+665.

Analysis.--Calcd. for C H O C, 69.4; H, 8.4. Found: C, 69.2; H, 8.5.

By replacing the acetic anhydride in the foregoing example by a molarequivalent amount of butyric anhydride, octanoyl chloride,trimethylacetyl, chloride, succinic anhydride, fi cyclopentylpropionylchloride, benzoyl chloride, p-nitrobenzoyl chloride, phenylacetylchloride, cinnamoyl chloride, p-chlorophenoxyacetic anhydride,3,4,5-trimethoxybenzoyl chloride, or a mixture of acetic anhydride andformic acid, there can be obtained, respectively,20:,3a,17fl-butyryloxy-4-androstene, 20,3C4, 173-octanoyloXy-4-androstene, 20,3oc,17/3 trimethylacetoXy-4-androstene,2a,3a,17/3-tris(,B-carboxypropionoxy)- 4-androstene,2a,3ot,17B-tris(,B-cyclopentylpropionoxy)-4- androstene,2a,3a,17/3-tribenzoyloxy-4-androstene, 20,3zx, 178-tris(p-nitrobenzoyloxy)-4-androstene, 2a,3a,17B-tris-(phenylacetoxy)-4-androstene, 211,311,175 tricinnamoyloxy-4-androstene,2ot,3a,17,8 tris(p chlorophenoxyacetoXy)-4-androstene,20:,3a,l'ifi-tris(3,4,5-trimethoxybenzoyloxy)-4-androstene, or20:,304,17,6-triform0xy-4-androstene.

EXAMlLE 3 20e35,]7fi-triacet0xy-4-andr0stene.-A mixture of 1.88

g. of 4-androstene-2rx,3 3,1'7fl-triol and 15 ml. of acetic' anhydridewas heated on a steam bath for four hours. The product was isolated andchromatographed on 70 g. of silica gel. A 1:4 ether-pentane mixtureeluted 1.22 g. of 2:1,3 3,17 3-triacetoXy-4-androstene in the form ofmassive prisms which, when twice recrystallized from methanol, melted at151.2-153.2 C. (corn),

4, 2. A compound having the formula OR CH3 P iZjJJQU v wherein R isselected from the group consisting of hydrogen and carboxylic acyl.

3. A compound having the formula I III) References Cited in the file ofthis patent UNITED STATES PATENTS Colton July 15, 1958 Sondheimer et a1Aug. 5, 1958

1. A MEMBER OF THE GROUP CONSISTING OF 4-ANDROSTENE2A,3,17$-TRIOL ANDCARBOXYLIC ACYL ESTERS THEREOF.